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NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys) AND Long QT syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 16, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000232889.11

Allele description [Variation Report for NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)]

NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)

Gene:
CACNA1C:calcium voltage-gated channel subunit alpha1 C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.33
Genomic location:
Preferred name:
NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)
Other names:
p.R518C:CGC>TGC
HGVS:
  • NC_000012.12:g.2566465C>T
  • NG_008801.2:g.600680C>T
  • NM_000719.7:c.1552C>TMANE SELECT
  • NM_001129827.2:c.1552C>T
  • NM_001129829.2:c.1552C>T
  • NM_001129830.3:c.1552C>T
  • NM_001129831.2:c.1552C>T
  • NM_001129832.2:c.1552C>T
  • NM_001129833.2:c.1552C>T
  • NM_001129834.2:c.1552C>T
  • NM_001129835.2:c.1552C>T
  • NM_001129836.2:c.1552C>T
  • NM_001129837.2:c.1552C>T
  • NM_001129838.2:c.1552C>T
  • NM_001129839.2:c.1552C>T
  • NM_001129840.2:c.1552C>T
  • NM_001129841.2:c.1552C>T
  • NM_001129842.2:c.1552C>T
  • NM_001129843.2:c.1552C>T
  • NM_001129844.2:c.1543C>T
  • NM_001129846.2:c.1552C>T
  • NM_001167623.2:c.1552C>T
  • NM_001167624.3:c.1552C>T
  • NM_001167625.2:c.1552C>T
  • NM_199460.4:c.1552C>T
  • NP_000710.5:p.Arg518Cys
  • NP_000710.5:p.Arg518Cys
  • NP_001123299.1:p.Arg518Cys
  • NP_001123299.1:p.Arg518Cys
  • NP_001123301.1:p.Arg518Cys
  • NP_001123302.1:p.Arg518Cys
  • NP_001123302.2:p.Arg518Cys
  • NP_001123303.1:p.Arg518Cys
  • NP_001123304.1:p.Arg518Cys
  • NP_001123305.1:p.Arg518Cys
  • NP_001123306.1:p.Arg518Cys
  • NP_001123307.1:p.Arg518Cys
  • NP_001123308.1:p.Arg518Cys
  • NP_001123309.1:p.Arg518Cys
  • NP_001123310.1:p.Arg518Cys
  • NP_001123311.1:p.Arg518Cys
  • NP_001123312.1:p.Arg518Cys
  • NP_001123312.1:p.Arg518Cys
  • NP_001123313.1:p.Arg518Cys
  • NP_001123314.1:p.Arg518Cys
  • NP_001123315.1:p.Arg518Cys
  • NP_001123316.1:p.Arg515Cys
  • NP_001123318.1:p.Arg518Cys
  • NP_001161095.1:p.Arg518Cys
  • NP_001161096.2:p.Arg518Cys
  • NP_001161097.1:p.Arg518Cys
  • NP_955630.3:p.Arg518Cys
  • LRG_334t1:c.1552C>T
  • LRG_334t2:c.1552C>T
  • LRG_334t3:c.1552C>T
  • LRG_334t4:c.1552C>T
  • LRG_334:g.600680C>T
  • LRG_334p1:p.Arg518Cys
  • LRG_334p2:p.Arg518Cys
  • LRG_334p3:p.Arg518Cys
  • LRG_334p4:p.Arg518Cys
  • NC_000012.11:g.2675631C>T
  • NM_000719.6:c.1552C>T
  • NM_001129827.1:c.1552C>T
  • NM_001129830.1:c.1552C>T
  • NM_001129840.1:c.1552C>T
Protein change:
R515C; ARG518CYS
Links:
OMIM: 114205.0016; dbSNP: rs786205748
NCBI 1000 Genomes Browser:
rs786205748
Molecular consequence:
  • NM_000719.7:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129827.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129829.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129830.3:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129831.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129832.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129833.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129834.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129835.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129836.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129837.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129838.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129839.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129840.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129841.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129842.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129843.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129844.2:c.1543C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129846.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167623.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167624.3:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167625.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199460.4:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000285587Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 16, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.

Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, Johnson AJ, Kanter R, Ackerman MJ.

Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1122-32. doi: 10.1161/CIRCEP.115.002745. Epub 2015 Aug 7.

PubMed [citation]
PMID:
26253506
PMCID:
PMC5094060

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000285587.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 518 of the CACNA1C protein (p.Arg518Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (LQTS), hypertrophic cardiomyopathy (HCM) and septal defects (CHD) (PMID: 26253506; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190642). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1C protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 26253506). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024